16-30960489-A-G

Variant names:

• chr16-30960489-A-G
• rs2054213
• NM_014712.3:c.247-778A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014712.3(SETD1A):​c.247-778A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,026 control chromosomes in the GnomAD database, including 23,551 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (23551 hom., cov: 32)
• Consequence: SETD1A NM_014712.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.827
• Publications: 25 publications found

Genes affected

SETD1A (HGNC:29010): (SET domain containing 1A, histone lysine methyltransferase) The protein encoded by this gene is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at Lys4. Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to generally mark the transcription start sites of active genes. The protein contains SET domains, a RNA recognition motif domain and is a member of the class V-like SAM-binding methyltransferase superfamily. [provided by RefSeq, Dec 2016]

SETD1A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with speech impairment and dysmorphic facies

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• epilepsy, early-onset, with or without developmental delay

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1A	NM_014712.3	c.247-778A>G		intron_variant	Intron 3 of 18	ENST00000262519.14	NP_055527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1A	ENST00000262519.14	c.247-778A>G		intron_variant	Intron 3 of 18	1	NM_014712.3	ENSP00000262519.8
SETD1A	ENST00000684162.1	c.247-778A>G		intron_variant	Intron 3 of 18			ENSP00000507683.1
SETD1A	ENST00000710314.1	c.247-778A>G		intron_variant	Intron 3 of 18			ENSP00000518195.1
SETD1A	ENST00000682768.1	c.247-778A>G		intron_variant	Intron 3 of 5			ENSP00000508271.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80366 AN: 151906 Hom.: 23533 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.736

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.594

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80430 AN: 152026 Hom.: 23551 Cov.: 32 AF XY: 0.530 AC XY: 39409 AN XY: 74330

African (AFR) AF: 0.279 AC: 11538 AN: 41424

American (AMR) AF: 0.570 AC: 8702 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2389 AN: 3472

East Asian (EAS) AF: 0.906 AC: 4697 AN: 5186

South Asian (SAS) AF: 0.311 AC: 1498 AN: 4820

European-Finnish (FIN) AF: 0.668 AC: 7056 AN: 10566

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42518 AN: 67972

Other (OTH) AF: 0.590 AC: 1241 AN: 2102

Alfa AF: 0.615 Hom.: 62792

Bravo AF: 0.520

Asia WGS AF: 0.547 AC: 1907 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.48
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2054213; hg19: chr16-30971810;